EFFECTS OF RECOMBINANT HUMAN STEM CELL FACTOR ON HEMATOPOIESIS

重组人干细胞因子对造血的影响

• 批准号: 6116371
• 负责人: ROBERT GOFF ANDREWS
• 金额: $ 8.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116371
• 关键词: Mammalia; Primates; animal tissue; biotechnology; hematology; lymphatic system; transplantation

The goal of this project is to study the in vivo and in vitro biological effects on hematopoiesis of recombinant human stem cell factor (rhSCF), a ligand for the human c-kit molecule, a cell surface receptor with tyrosine kinase activity. In vitro, SCF by itself stimulates little proliferation of human and baboon marrow hematopoietic colony-forming cells (CFC), but does have stimulating effects when combined with other hematopoietic growth factors, including IL-3, G-CSF, GM-CSF, and Epo. In vivo, SCF stimulates a dose-dependent leukocytosis, with increases in neutrophils, monocytes, eosinophils, basophils, and T and B lymphocytes in the blood. SCF also stimulates a reticulocytosis and increases in the numbers of red blood cells and in hematocrit. In marrow, SCF stimulates a dose-dependent increase in cellularity and morphologically immature erythroid and granulocytic cells. Importantly, SCF increases the number of hematopoietic colony-forming progenitor cells in marrow and blood. The number of progenitor cells in blood increases from 10-fold to >1000-fold in animals given SCF at a dose of 200 g/Kg/day, with an associated increase in numbers of CD34+ cells in blood. We have also shown that transplantable cells capable of rescuing and reconstituting lymphohematopoiesis in lethally irradiated baboons are increased in the blood by treatment with high doses of SCF. SCF also has in vivo synergy with G-CSF. SCF at 25 g/kg/day, which alone does not stimulate a leukocytosis or an increase in peripheral blood progenitors, when administered with G-CSF increases the rate at which circulating WBC increase as well as the maximum WBC achieved, compared with G-CSF alone. Most importantly, this dose of SCF when combined with G-CSF dramatically enhances the circulation of progenitor cells as well as marrow repopulating cells compared with G-CSF alone. Animals transplanted with blood cells collected during stimulation with the combination of SCF plus G-CSF engraft much more rapidly than do animals transplanted with cells collected during stimulation with G-CSF alone. Studies are in progress to determine if SCF, in combination with other growth factors, can be used to expand the number of progenitors from marrow and blood in vitro and if these expanded cells can engraft lethally irradiated baboons.

该项目的目标是研究重组人干细胞因子（rhSCF）对造血的体内和体外生物效应，rhSCF是人c-kit分子的配体，是具有酪氨酸激酶活性的细胞表面受体。 在体外，SCF 本身对人类和狒狒骨髓造血集落形成细胞 (CFC) 的增殖影响很小，但与其他造血生长因子（包括 IL-3、G-CSF、GM-CSF 和埃波。在体内，SCF 刺激剂量依赖性白细胞增多，导致血液中中性粒细胞、单核细胞、嗜酸性粒细胞、嗜碱性粒细胞以及 T 和 B 淋巴细胞增加。 SCF 还刺激网织红细胞增多并增加红细胞数量和血细胞比容。 在骨髓中，SCF 刺激细胞结构和形态上未成熟的红系细胞和粒细胞的剂量依赖性增加。重要的是，SCF 增加了骨髓和血液中造血集落形成祖细胞的数量。 在以 200 g/Kg/天的剂量给予 SCF 的动物中，血液中的祖细胞数量从 10 倍增加到 >1000 倍，同时血液中的 CD34+ 细胞数量也相应增加。 我们还表明，通过高剂量的 SCF 治疗，血液中能够挽救和重建受到致命辐射的狒狒的淋巴造血功能的可移植细胞会增加。 SCF 还与 G-CSF 具有体内协同作用。 与 G-CSF 相比，25 g/kg/天的 SCF 单独使用不会刺激白细胞增多或外周血祖细胞增加，但与 G-CSF 一起施用时，可增加循环 WBC 增加的速率以及达到的最大 WBC单独脑脊液。 最重要的是，与单独使用 G-CSF 相比，该剂量的 SCF 与 G-CSF 联合使用可显着增强祖细胞以及骨髓再生细胞的循环。 移植有在SCF加G-CSF组合刺激期间收集的血细胞的动物比移植有在单独用G-CSF刺激期间收集的细胞的动物移植得更快。目前正在进行研究以确定 SCF 与其他生长因子结合是否可用于在体外扩增来自骨髓和血液的祖细胞数量，以及这些扩增的细胞是否可以植入受到致命辐射的狒狒。